2.A.58 The Phosphate:Na+ Symporter (PNaS) Family

The PNaS family includes several closely related, functionally characterized, sodium-dependent, inorganic phosphate (Pi) transporter (NPT2) proteins from mammals. Other animals, including fish and the worm, C. elegans, possess functionally uncharacterized homologues. One closely related bacterial protein, NptA of Vibrio cholerae, resembles the animal proteins to a much greater degree (34% identity; 51% similarity to many mammalian Npt2 symporters) than to any other bacterial homologue, and it may therefore have been obtained by lateral transfer from a eukaryotic source. Distantly related bacterial proteins are found in many bacteria including E. coli(543 aas; spP32683; 8 putative TMSs) and Bacillus subtilis(310 aas; spP54463; 8 putative TMSs). The bacterial homologue, NptA of V. cholerae has 10 putative TMSs. The well-characterized mammalian proteins are found in renal (IIa isoform) and intestinal (IIb isoform) brush border membranes and are about 640 amino acyl residues long with 8-12 putative TMSs. The N- and C-termini are in the cytoplasm, and a large hydrophilic loop is localized between TMSs 3 and 4. While IIa isoforms are pH-dependent, IIb isoforms are pH-independent (de la Horra et al., 2000).

Mammalian porters of the PNaS family may catalyze cotransport of 3 Na+ with inorganic phosphate. In response to parathyroid hormone and dietary inorganic phosphate, the renal cotransporter is rapidly inserted into and retrieved from the renal brush border membrane in a fashion similar to that by which the glucose transporter (Glut4) (2.A.1.1) is regulated by insulin and aquaporins 1 and 2 (1.A.8.1) are regulated by vasopressin (Levi et al., 1999). The renal type IIa PNaS member is a functional monomer (Kohler et al., 2001), but it interacts with PDZ proteins which probably mediate apical sorting, parathyroid hormone-controlled endocytosis and/or lysosomal sorting of internalized transporter (Gisler et al., 2001). 

A single organism may have multiple paralogues of the PNaS family. All of these proteins exhibit an internal repeat that probably arose by a tandem intragenic duplication event. Their properties and mechanisms of action have been reviewed (Forster 2018).

The transport reaction catalyzed by the mammalian proteins is:

Pi (out) + 3 Na+ (out) ⇌ Pi (in) + 3 Na+ (in).



This family belongs to the .

 

References:

Bakouh, N., B. Chérif-Zahar, P. Hulin, D. Prié, G. Friedlander, A. Edelman, and G. Planelles. (2012). Functional Interaction between CFTR and the Sodium-Phosphate Co-Transport Type 2a in Xenopus laevis Oocytes. PLoS One 7: e34879.

Chen, P., Q. Tang, and C. Wang. (2016). Characterizing and evaluating the expression of the type IIb sodium-dependent phosphate cotransporter (slc34a2) gene and its potential influence on phosphorus utilization efficiency in yellow catfish (Pelteobagrus fulvidraco). Fish Physiol Biochem 42: 51-64.

Chen, P., Y. Huang, A. Bayir, and C. Wang. (2017). Characterization of the isoforms of type IIb sodium-dependent phosphate cotransporter (Slc34a2) in yellow catfish, Pelteobagrus fulvidraco, and their vitamin D3-regulated expression under low-phosphate conditions. Fish Physiol Biochem 43: 229-244.

Collins, J.F. and F.K. Ghishan. (1994). Molecular cloning, functional expression, tissue distribution, and in situ hybridization of the renal sodium phosphate (Na+/Pi) transporter in the control and hypophosphatemic mouse. FASEB J. 8: 862-868.

De la Horra, C., N. Hernando, G. Lambert, I. Forster, J. Biber, and H. Murer. (2000). Molecular determinants of pH sensitivity of the type IIa Na/P(i) cotransporter. J. Biol. Chem. 275: 6284-6287.

Ebert, M., S. Laaß, M. Burghartz, J. Petersen, S. Koßmehl, L. Wöhlbrand, R. Rabus, C. Wittmann, P. Tielen, and D. Jahn. (2013). Transposon mutagenesis identified chromosomal and plasmid genes essential for adaptation of the marine bacterium Dinoroseobacter shibae to anaerobic conditions. J. Bacteriol. 195: 4769-4777.

Fenollar-Ferrer, C., I.C. Forster, M. Patti, T. Knoepfel, A. Werner, and L.R. Forrest. (2015). Identification of the First Sodium Binding Site of the Phosphate Cotransporter NaPi-IIa (SLC34A1). Biophys. J. 108: 2465-2480.

Forster, I.C. (2018). The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. Pflugers Arch. [Epub: Ahead of Print]

Ghezzi C., Murer H. and Forster IC. (2009). Substrate interactions of the electroneutral Na+-coupled inorganic phosphate cotransporter (NaPi-IIc). J Physiol. 587(Pt 17):4293-307.

Gisler, S.M., I. Stagljar, M. Traebert, D. Bacic, J. Biber, and H. Murer. (2001). Interaction of the type IIa Na/Pi cotransporter with PDZ proteins. J. Biol. Chem. 276: 9206-9213.

Kohler, K., I.C. Forster, G. Lambert, J. Biber, and H. Murer. (2001). The functional unit of the renal type IIa Na+/Pi cotransporter is a monomer. J. Biol. Chem 275: 26113-26120.

Lebens, M., P. Lundquist, L. Söderlund, M. Todorovic, and N.I. Carlin. (2002). The nptA gene of Vibrio cholerae encodes a functional sodium-dependent phosphate cotransporter homologous to the type II cotransporters of eukaryotes. J. Bacteriol. 184: 4466-4474.

Levi, M., S.A. Kempson, M. Lötscher, J. Biber, and H. Murer. (1996). Molecular regulation of renal phosphate transport. J. Memb. Biol. 154: 1-9.

Magagnin, S., A. Werner, D. Markovich, V. Sorribas, G. Stange, J. Biber, and H. Murer. (1993). Expression cloning of human and rat renal cortex sodium-phosphorus cotransport. Proc. Natl. Acad. Sci. USA 90: 5979-5983.

Mamonova, T., Q. Zhang, J.A. Khajeh, Z. Bu, A. Bisello, and P.A. Friedman. (2015). Canonical and Noncanonical Sites Determine NPT2A Binding Selectivity to NHERF1 PDZ1. PLoS One 10: e0129554.

Motomura, K., R. Hirota, N. Ohnaka, M. Okada, T. Ikeda, T. Morohoshi, H. Ohtake, and A. Kuroda. (2011). Overproduction of YjbB reduces the level of polyphosphate in Escherichia coli: a hypothetical role of YjbB in phosphate export and polyphosphate accumulation. FEMS Microbiol. Lett. 320: 25-32.

Murer, H., N. Hernando, I. Forster, and J. Biber. (2000). Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol. Rev. 80: 1373-1409.

Patti, M., C. Fenollar-Ferrer, A. Werner, L.R. Forrest, and I.C. Forster. (2016). Cation Interactions and Membrane Potential Induce Conformational Changes in NaPi-IIb. Biophys. J. 111: 973-988.

Radanovic, T., S.M. Gisler, J. Biber, and H. Murer. (2006). Topology of the type IIa Na+/P(i) cotransporter. J. Membr. Biol. 212: 41-49.

Segawa, H., I. Kaneko, A. Takahashi, M. Kuwahata, M. Ito, I. Ohkido, S. Tatsumi, and K. Miyamoto. (2002). Growth-related renal type II NaPi cotransporter. J. Biol. chem. 277: 19665-19672.

Stechman, M.J., N.Y. Loh, and R.V. Thakker. (2007). Genetics of hypercalciuric nephrolithiasis: renal stone disease. Ann. N.Y. Acad. Sci. 1116: 461-484.

Verri, T., D. Markovich, C. Perego, F. Norbis, G. Stange, V. Sorribas, J. Biber, and H. Murer. (1995). Cloning of a rabbit renal Na+-Pi cotransporter, which is regulated by dietary phosphate. Am. J. Physiol. 268: F626-F633.

Zhifeng, X., F. Rejun, H. Longchang, and S. Wenqing. (2012). Molecular cloning and functional characterization of swine sodium dependent phosphate cotransporter type II b (NaPi-IIb) gene. Mol Biol Rep 39: 10557-10564.

Examples:

TC#NameOrganismal TypeExample
2.A.58.1.1

Renal Na+-dependent phosphate transport protein 2 (NPT2). Catalyzes 3Na+:1Pi symport (Ghezzi et al., 2009).

Animals

NPT2 of Rattus norvegicus (Q60825)

 
2.A.58.1.2

Na+-dependent phosphate transporter, NptA (Lebens et al. 2002).

Bacteria

NptA of Vibrio cholerae

 
2.A.58.1.3

Renal Na+/phosphate electroneutral symporter, NPTIIc, NPT2a or NaPi-IIc; responsible for hypophosphatemic hypercalciuric nephrolithiasis associated with rickets (Stechman et al., 2007). Catalyzes 2Na+:1Pi symport (Ghezzi et al., 2009). Interacts functionally with CFTR (Bakouh et al., 2012). Also interacts with PDZ1 but not PDZ2 of NHERF1 (Mamonova et al. 2015).

Animals

SLC34A3 of Homo sapiens

 
2.A.58.1.4

Sodium-dependent phosphate transport protein 2B (Sodium-phosphate transport protein 2B) (Na+-dependent phosphate cotransporter 2B) (NaPi-2B) (Sodium/phosphate cotransporter 2B) (Na+/Pi cotransporter 2B) (NaPi-2b) (Solute carrier family 34 member 2).  The membrane potential and cation interactions induce large-scale structural rearrangements of the protein (Patti et al. 2016).

Animals

SLC34A2 of Homo sapiens

 
2.A.58.1.5

Sodium-dependent phosphate transport protein 2A (Sodium-phosphate transport protein 2A; Na+-dependent phosphate cotransporter 2A; NaPiIIa; NaPi-3; NaPi-2a) (Solute carrier family 34 member 1; SLC34A1) of 639 aas and 12 TMSs.  Co-transports 3 Na+ with 1 divalent phosphate anion.  There are 3 Na+ binding sites, N1 (binds Na+ or Li+), N2 and N3, (both of which are Na+-specific); residues comprising N1 have been identified (Fenollar-Ferrer et al. 2015).

Animals

SLC34A1 of Homo sapiens

 
2.A.58.1.6

Sodium-dependent phosphate transporter, NaPi-IIA. The stoichiometry is probably 3 Na+ to 1 phosphate molecules.  Orthologous to 2.A.58.1.4.  Predicted to have 12 TMSs with both the N- and C-termini intracellular (Radanovic et al. 2006).  The Km for phosphate is 80 μM (Zhifeng et al. 2012). 

Animals

NaPi-IIB of Sus scrofa

 
2.A.58.1.7

Sodium:phosphate cotransporter of 621 aas and 10 TMSs, NaPi-IIb (SLC34a2).  The amino acid sequence showed 79.0 and 70.9% sequence identity to the Astyanax mexicanus and Pundamilia nyererei orthologues, respectively. The  protein had eight predicted TMSs, with the amino and carboxy termini intracellular (Chen et al. 2016). Three isoforms have been evaluated with respect to the effects of diatary inorganic phosphate and vitamin D in several tisseues have been determined (Chen et al. 2017).

NaPi-IIb of Tachysurus fulvidraco (Yellow catfish) (Pimelodus fulvidraco)

 
Examples:

TC#NameOrganismal TypeExample
2.A.58.2.1

Inorganic phosphate transporter, YjbB.  May be able to catalyze both uptake and efflux (Motomura et al. 2011; Ebert et al. 2013).

Bacteria

YjbB of E. coli (P0AF43)

 
2.A.58.2.2

8 TMS NaPi co-transporter with a PhoU C-terminal domain

Fusobacteria

NaPi transporter of Fusobacterium nucleatum

 
2.A.58.2.3

NaPi cotransporter with 8 TMSs and a C-terminal PhoU domain

Firmicutes

NaPi transporter of Natranaeoblius thermophilus

 
2.A.58.2.4

Na+/Pi cotransporter of 616 aas (Ebert et al. 2013).

Proteobacteria

Phosphate transporter of Dinoroseobacter shibae

 
2.A.58.2.5

Uncharacterized protein of 370 aas and 9 TMSs

UP of Salinarchaeum sp. Harcht-Bsk1

 
2.A.58.2.6

Putative Na+-dependent phosphate symporter of 558 aas and 9 TMSs.

PNaS family member of Methanocella arvoryzae